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Melanomas Are Comprised of Multiple Biologically Distinct Categories

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Melanomas Are Comprised of Multiple Biologically Distinct Categories Melanomas are comprised of multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain of function mutations in one of several primary oncogenes, typically leading to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about pathogenesis, clinical, histological and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework. THE MOLECULAR PATHOLOGY OF MELANOMA: AN INTEGRATED TAXONOMY OF MELANOCYTIC NEOPLASIA Boris C. Bastian Corresponding Author: Boris C. Bastian, M.D. Ph.D. Gerson & Barbara Bass Bakar Distinguished Professor of Cancer Biology Departments of Dermatology and Pathology University of California, San Francisco UCSF Cardiovascular Research Institute 555 Mission Bay Blvd South Box 3118, Room 252K San Francisco, CA 94158-9001 [email protected] Key words: Genetics Pathogenesis Classification Mutation Nevi Table of Contents Molecular pathogenesis of melanocytic neoplasia .................................................... 1 Classification of melanocytic neoplasms ........................................................................... 2 Melanocytic neoplasms originating from epithelial melanocytes ...................................... 4 Melanocytic neoplasms on hair-bearing skin ....................................................................... 4 Melanomas on sun-exposed skin without cumulative sun-induced damage (non-CSD) ............... 4 Common acquired nevi .............................................................................................................. 5 Tumor suppressive mechanisms at the junction between nevi and melanomas ...................... 6 Dysplastic nevi ........................................................................................................................... 9 Spitz tumors ............................................................................................................................. 10 Pediatric melanoma ................................................................................................................. 11 The role of UV radiation and skin pigmentation ...................................................................... 12 Melanomas on skin with cumulative sun-induced damage (CSD melanomas) ....................... 14 Desmoplastic melanomas ........................................................................................................ 14 Acral and mucosal melanomas ................................................................................................ 14 Melanocytic neoplasms originating from melanocytes not associated with epithelia ...... 16 Congenital nevi ........................................................................................................................ 16 Blue nevi and related neoplasms ............................................................................................. 17 Melanocytoma of the central nervous system ........................................................................ 18 Uveal melanoma ...................................................................................................................... 19 Sidebar ........................................................................................................................... 20 Melanocyte development and the tanning response .................................................................. 20 Summary points .............................................................................................................. 20 Abbreviations ................................................................................................................. 20 Acknowledgements ........................................................................................................ 21 References .............................................................................................................. 22 Classification of melanocytic neoplasms Melanocytes can give rise to a diverse set of neoplasms with varying anatomic distribution, clinical features, histopathological appearance, and biologic behavior. While melanocytes are most abundant in the skin where they play a critical role in skin pigmentation and sun protection, they are present in other locations throughout the body where they have additional, less well understood functions. While melanocytic neoplasms most frequently arise from melanocytes in the skin they can also arise from autochthonous melanocytes from numerous internal organs including the central nervous system (CNS). As a rule, benign neoplasms of melanocytic lineage are termed melanocytic nevi (the plural of nevus) and malignant ones are termed melanomas; the often-used term “malignant melanoma” thus represents a tautology. While melanomas can arise from nevi, as can be inferred from the presence of an adjacent nevus remnant that is contiguous with a melanoma, most primary melanomas do not show such an associated precursor nevus. In part this is because the precursor nevus was overgrown by the melanoma during its progression, but in many instances there most likely was no detectable benign precursor state. It has long been noted that melanoma is comprised of different subtypes, depending on where they arise and that their pathogenesis varies. The current WHO classification (1) is based on the melanoma classification proposed by Clark and colleagues (2) more than 30 years ago, which uses morphologic aspects of the early (radial) growth phase and the body site of the primary melanoma to distinguish four main types: superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), nodular melanoma (NM) and acral-lentiginous melanoma (ALM). The system captures archetypical patterns of clinical and histological presentation, however a portion of melanomas cannot be unequivocally categorized in any of the categories (3) and its impact on clinical care, in particular that of advanced disease has been limited. Over the last two decades tremendous progress has been made in uncovering genetic alterations in melanocytic neoplasia and an expanding panel or recurrent driver mutations that activate specific oncogenes or inactivate tumor suppressor genes is emerging. Remarkably, many of the mutations are found in association with specific clinical or histopathological subsets of lesions, strongly supporting the notion of biologically distinct types of melanocytic neoplasms. This is true for melanomas as well as for melanocytic nevi, which express a similar diversity in clinical appearance and histomorphology, age of onset, anatomic site of the tumor, and the genetic alterations present. A desirable classification system separates individual disease states by considering differences in cell of origin, pathogenesis, clinical and histologic aspects, genetic alterations etc. It can serve as a framework to develop refined approaches for primary prevention, objective diagnostic and staging algorithms, and tailored therapeutic strategies. Such a taxonomy differs from current approaches which rely primarily on one of these dimensions, histology or mutation status, and instead integrates multiple aspects to capture individual disease subtypes. The organizing principle for this overview is the current, but still incomplete, clinical and genetic data that is available in varying detail across the broad phenotypic spectrum of melanomagenesis. The proposed taxa are separated in one dimension. For some taxa distinct evolutionary stages - reaching from benign, intermediate, to malignant – are separated in the second dimension (figure 1). The guiding principles for distinguishing taxa will be genetic alterations that arise early during progression, clinical or histologic features of the primary tumor, and characteristics of the host such as age of onset, ethnicity, skin type, and as the role of environmental factors such a the role UV radiation. Mutations common to all progression steps within a taxon will be considered probable initiating oncogenic events. They are gain of function mutations in oncogenes that tend to occur in a mutually exclusive pattern. The known initiating oncogenic events in melanocytic neoplasia are listed in table 1. By contrast, oncogenic events that mark the transition to the next progression stage within a given taxon will be considered secondary (or tertiary) oncogenic events. These are commonly loss of function alterations of tumor suppressor genes such as CDNK2A, TP53, PTEN, or BAP1, some of which are also encountered as germ line alterations predisposing to syndromes with various types of melanocytic neoplasms (table 2). Somatic alterations considered progression events are listed in table 3. As a consequence, initiating oncogenic events will be most valuable for separating classes, whereas later events serve to separate progression steps within classes. Primary and secondary oncogenic events will not necessarily have a one-to-one relationship to either taxa or the progression steps within a taxon. Some classes may
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